Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium

Schuler, Bryce A.; Habermann, Arun C.; Plosa, Erin J.; Taylor, Chase J.; Jetter, Christopher S.; Negretti, Nicholas M.; Kapp, Meghan E.; Benjamin, John T.; Gulleman, Peter M.; Nichols, David S.; Braunstein, Lior Z.; Hackett, Alice N.; Koval, Michael; Guttentag, Susan H.; Blackwell, Timothy S.; Webber, Steven A.; Banovich, Nicholas E.; Kropski, Jonathan A.; Sucre, Jennifer M. S.

doi:10.1172/jci140766

Cited by 121 publications

(117 citation statements)

References 31 publications

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“…To confirm lack of ACE2 expression in murine lungs, we performed immunoblot analysis which demonstrated ACE2 expression in the control kidney homogenate, but not in whole lung homogenates from 1-d-old, 7-d-old, 14-d-old, or adult mice ( Fig 4D ). In contrast, consistent with the data from NHP lungs and a recent paper that was published during the preparation of this manuscript [ 40 ], TMPRSS2 expression was detected in lungs from all age groups in a pattern consistent with developmental upregulation, with detection of the highest TMPRSS2 levels in adult lungs compared to newborn lungs ( Fig 4D and 4E ).…”

Section: Resultssupporting

confidence: 91%

Comparative analysis of ACE2 protein expression in rodent, non-human primate, and human respiratory tract at baseline and after injury: A conundrum for COVID-19 pathogenesis

et al. 2021

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Angiotensin converting enzyme 2 (ACE2) is the putative functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current literature on the abundance and distribution of ACE2 protein in the human respiratory tract is controversial. We examined the effect of age and lung injury on ACE2 protein expression in rodent and non-human primate (NHP) models. We also examined ACE2 expression in human tissues with and without coronavirus disease 19 (COVID-19). ACE2 expression was detected at very low levels in preterm, but was absent in full-term and adult NHP lung homogenates. This pattern of ACE2 expression contrasted with that of transmembrane protease serine type 2 (TMPRSS2), which was significantly increased in full-term newborn and adult NHP lungs compared to preterm NHP lungs. ACE2 expression was not detected in NHP lungs with cigarette smoke-induced airway disease or bronchopulmonary dysplasia. Murine lungs lacked basal ACE2 immunoreactivity, but responded to hyperoxia, bacterial infection, and allergen exposure with new ACE2 expression in bronchial epithelial cells. In human specimens, robust ACE2 immunoreactivity was detected in ciliated epithelial cells in paranasal sinus specimens, while ACE2 expression was detected only in rare type 2 alveolar epithelial cells in control lungs. In autopsy specimens from patients with COVID-19 pneumonia, ACE2 was detected in rare ciliated epithelial and endothelial cells in the trachea, but not in the lung. There was robust expression of ACE2 expression in F344/N rat nasal mucosa and lung specimens, which authentically recapitulated the ACE2 expression pattern in human paranasal sinus specimens. Thus, ACE2 protein expression demonstrates a significant gradient between upper and lower respiratory tract in humans and is scarce in the lung. This pattern of ACE2 expression supports the notion of sinonasal epithelium being the main entry site for SARS-CoV-2 but raises further questions on the pathogenesis and cellular targets of SARS-CoV-2 in COVID-19 pneumonia.

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Section: Resultssupporting

confidence: 91%

Comparative analysis of ACE2 protein expression in rodent, non-human primate, and human respiratory tract at baseline and after injury: A conundrum for COVID-19 pathogenesis

et al. 2021

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“…50 However, increased TMPRSS2 expression with aging was reported in mice and humans. 51 The difference between this study and ours may be due to the age range and the type cell investigated (type I vs type II pneumocytes). We also observed that the percentage of TMPRSS2-expressing type II pneumocytes was higher in men than women.…”

Section: Discussioncontrasting

confidence: 61%

Renin-Angiotensin System Blockade Influences ACE2 in Human Type II Pneumocytes

Silva

Falcoff

Corradi

et al. 2021

Preprint

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Rationale—Angiotensin converting enzyme (ACE) 2 and the transmembrane protease serine 2 (TMPRSS2) are key for cellular entry of the type 2 coronavirus that causes severe acute respiratory syndrome (SARS-CoV2), the etiological agent of coronavirus-19 disease (COVID-19). There has been a growing concern that renin-angiotensin system (RAS) blockade with ACE inhibitors (ACEIs) or type 1 angiotensin (Ang II) receptor blockers (ARBs) increases ACE2 expression and then elevate patient susceptibility to SARS-CoV-2. However, evidence about RAS blockade and ACE2 in human lung are lacking.Objective– To investigate RAS blockade on ACE2 and TMPRSS2 in type II pneumocytes of human lung parenchymal of untreated and ACEI/ARB-treated hypertensive subjects.Methods and Results– ACE2 and TMPRSS2 protein expression were measured by immunohistochemistry. We found that smoking and RAS blockade influence on the percentage of human ACE2-expressing type II pneumocytes (p= 0.026). Smokers subjects under RAS blockade treatment exhibited higher percentage of ACE2-expressing type II pneumocytes than normotensive ones. Within the ACEI/ARB-treated group, the percentage of ACE2-expressing type II pneumocytes was higher in smokers than never smokers. A significant association between ACE2 immunostaining intensity and smoking on subjects over 60 years old was found (p= 0.05): older smokers exhibited higher ACE2 protein levels compared to youngers. The percentage of TMPRSS2-expressing type II pneumocytes was greater in men than women (p= 0.026) and in subjects under 60 years old (p= 0.040) and trend to be higher in ACEI/ARB-treated subjects than normotensives (p= 0.060). A significant association between TMPRSS2 immunostaining intensity with smoking and age or with RAS blockade and age or with RAS blockade and smoking was observed. Older or smokers subjects under ACEI/ARB treatment exhibited higher TMPRSS2 protein levels than youngers or never smokers.Conclusions—ACE2 and TMPRSS2 are influenced by smoking and ACEI/ARB treatment. These findings help explain the increased susceptibility to COVID-19 in subjects with treated cardiovascular-related pathologies.

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“…Lung ACE2 expression has been shown to increase ~1.2-fold with every 10-year increase in age 44 . scRNA-seq of developing mouse lungs and temporally resolved RNA-in situ hybridization (ISH) analysis also found an age-related increase in TMPRSS2 expression 63 . Single-nucleus ATAC-seq (snATAC-seq) in human AT2 cells demonstrated age-associated changes in accessible chromatin around TMPRSS2 at sites harboring sequence motifs for multiple TFs, including forkhead box A (FOXA), C/EBPα, the proinflammatory factors STAT, IFN-regulatory factor (IRF), and AP-1, suggesting age-dependent inflammatory regulation of TMPRSS2 64 .…”

Section: Host Factor Expression Associated With Covid-19 Risk Factorsmentioning

confidence: 94%

From bedside to bench: regulation of host factors in SARS-CoV-2 infection

et al. 2021

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The zoonotic coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2), which causes COVID-19 (coronavirus disease-2019), has resulted in a pandemic. This has led to an urgent need to understand the molecular determinants of SARS-CoV-2 infection, factors associated with COVID-19 heterogeneity and severity, and therapeutic options for these patients. In this review, we discuss the role of host factors in SARS-CoV-2 infection and describe variations in host factor expression as mechanisms underlying the symptoms and severity of COVID-19. We focus on two host factors, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), implicated in SARS-CoV-2 infection. We also discuss genetic variants associated with COVID-19 severity revealed in selected patients and based on genome-wide association studies (GWASs). Furthermore, we highlight important advances in cell and chromatin biology, such as single-cell RNA and chromatin sequencing and chromosomal conformation assays, as methods that may aid in the discovery of viral–host interactions in COVID-19. Understanding how regulation of host factor genes varies in physiological and pathological states might explain the heterogeneity observed in SARS-CoV-2 infection, help identify pathways for therapeutic development, and identify patients most likely to progress to severe COVID-19.

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Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium

Cited by 121 publications

References 31 publications

Comparative analysis of ACE2 protein expression in rodent, non-human primate, and human respiratory tract at baseline and after injury: A conundrum for COVID-19 pathogenesis

Comparative analysis of ACE2 protein expression in rodent, non-human primate, and human respiratory tract at baseline and after injury: A conundrum for COVID-19 pathogenesis

Renin-Angiotensin System Blockade Influences ACE2 in Human Type II Pneumocytes

From bedside to bench: regulation of host factors in SARS-CoV-2 infection

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